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BioIVT has launched new cleanroom manufacturing space in Winchester, Va. A research partner and biospecimen solutions provider for drug and diagnostic development, the company partnered with Germfree, a provider of modular cleanroom infrastructure and services, to build the space, according to an Aug. 1, 2024 company press release.

The cleanroom comprises design and solutions from Germfree that boost BioIVT’s capabilities in cell and gene therapy (CGT) development. The integration of cleanroom processes will include BioIVT’s good manufacturing practice (GMP)-compliant raw materials for supporting CGTs, including Human AB serum.

“This facility will play a significant role in our expanding portfolio of GMP-compliant products,” said Parijat Jain, vice-president of Cell & Gene Therapy at BioIVT, in a company press release. “The cleanroom was designed in collaboration with Germfree, relying on their extensive expertise to build a facility that will support client-specific manufacturing requirements and configured for high-volume production enabling product use in late-stage clinical and commercial manufacturing. We continue to evolve and strengthen our support for the development of CGT research, and our future-ready cleanroom will provide expanded capabilities and access to developers.”

The new space is purpose built to support workflows for excipient and ancillary material bioprocessing. The cleanroom ensures quality and regulatory compliance and includes the following features:

qualified in accordance with FDA requirements

FDA-current GMP, International Organization for Standardization, ion selective electrode, Center for Disease Control–Biosafety in Microbiological and Biomedical Laboratories, and American Society for Testing and Materials tested

heating, ventilation, and air conditioning controls systems

high efficiency particulate air filtration.

"We at Germfree are honored to contribute to BioIVT's groundbreaking manufacturing space by providing our modular cleanroom technology,” said Kevin Kyle, CEO, Germfree, in the press release. “This new facility reflects BioIVT's dedication to advancing biospecimen solutions and scientific research, and the company’s deep experience in helping manufacturers build cutting-edge facilities. We are excited to support their mission and look forward to the innovative achievements that will benefit the life sciences and pharmaceutical industries, fostering advancements in research and development."

The cleanroom addition is the latest in a series of expansions BioIVT has pushed forward. In February 2024, the company increased its capacity for delivering readily available fresh, standard, and mobilized human leukopaks (1). The additional capacity further builds the company’s ability to scale its network of diverse and highly characterized cell donors. Earlier in October 2023, BioIVT expanded its biospecimen portfolio with the launch of its new Center for NeuroExcellence. Through this center, BioIVT can offer neurology researchers a single source from which they can obtain supplies, from controls to difficult-to-collect biofluid samples from populations with neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (2).

1. BioIVT. BioIVT Announces Expansive Fresh Leukopak Capability in Europe. Press Release, Feb. 22, 2024.
2. BioIVT. BioIVT Expands its Biospecimen Portfolio in Support of Neuroscience Research. Press Release, Oct. 27, 2023.

Articles

BioIVT opened new cleanroom manufacturing space, using Germfree’s technology to boost its capabilities for cell and gene therapy development.

Partners BioIVT and Germfree Open New Cleanroom Manufacturing Space at US Site

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

Communication between the manufacturing plant and retail stores. | Image Credit: © Cagkan - stock.adobe.com

The Bend, Ore., small molecules facility operated by Lonza is now offering clinical bottling and labeling capabilities, enhancing its support of customers focused on early stages of development, a press release from Lonza said on Aug. 6, 2024 (1).

Lonza said the addition of these services, along with the new equipment they require, builds upon the company’s investment in a dedicated early phase clinical manufacturing facility which was completed at the Bend site in 2022.

At that time, Paul Granberry, executive director and site head at Bend for Lonza Small Molecules, said the investment was a direct response to the evident needs of customers (2).

“We continue to observe strong demand from customers for providing early phase development support under accelerated timelines,” Granberry said in the press release. “With this dedicated facility, we further enhance our capabilities in this specific segment with improved speed of delivery.”

According to Lonza, the new equipment is not only able to clean, fill, cap, and seal as well as label, but also is capable of detecting defects in tablets and capsules (1). Ultimately, the company said, these enhanced service offerings will accelerate deliveries of various products to clinical trial centers, providing a more immediate benefit to the customer.

“Lonza’s drug product formulation and development services, offered from our site in Bend, support clinical and commercial development and manufacturing,” Matthew Ferguson, senior director of product development for Lonza Small Molecules, said in the release. “The new bottling equipment for filling tablets and powder-filled capsules further enhances our ability to support customers looking to accelerate their candidate pathway through Phase I and II clinical trials and beyond.”

The bottling and labeling capabilities will be just one of the more than 80 programs supported at the Bend site, which has operated as the company’s self-described “center of excellence” for bioavailability enhancement and inhaled delivery, in the areas of pharmacokinetic modulating and solubility problem-solving, for more than 45 years (1). Lonza’s website states its clinical trial services provide access to, and packaging and distribution of, a full range of solid oral dosage forms under current good manufacturing practice (CGMP) conditions (3).

Among the other services offered by Lonza in Bend are seven GMP suites and various capability enhancements for the purposes of development and clinical manufacturing of drug products and drug product intermediates.

This announcement follows Lonza’s March 2024 acquisition of a former Roche commercial biologics manufacturing site in Vacaville, Calif., at a price of $1.2 billion, and an additional $557 million investment into upgrading the facility and enhancing its capabilities (4).

1. Lonza. Lonza Upgrades Clinical Manufacturing Services at Bend (US) Site to Include Bottling and Labeling Capabilities. Press Release, Aug. 6, 2024.
2. Lonza. Lonza Completes Dedicated Early Clinical Phase Development and Manufacturing Facility in Bend (OR). Press Release, June 1, 2022.
3. Lonza. Clinical Packaging, Labelling, and Supply Services. 

 (accessed Aug. 6, 2024).
4. Mirasol, F. 

Lonza Acquires Roche’s US Commercial Biologics Manufacturing Site for $1.2 Billion.

The new additions to the company’s equipment at its early phase clinical manufacturing facility in Oregon will allow for cleaning, filling, capping, and sealing, and also detecting defects in drug products.

Lonza Adds Bottling, Labeling Capabilities to Clinical Manufacturing Services at US Site

Hand shaking which print screen on wooden cube block in front of human icon for business deal and agreement concept. | Image Credit: © Dilok - stock.adobe.com

In a press release on Aug. 5, 2024, Cambridge, UK-based Cresset said it would be expanding its global collaboration with Enamine in the field of targeted protein degradation (TPD) (1). TPD is a research strategy which, Cresset said, boasts ever-expanding applications in both chemical probe and therapeutic agent development.

Proteolysis-targeting chimeras (PROTACs), which consist of a protein of interest (POI)-binding ligand and E3-ligase ligand joined by a linker, are a major class of small molecules commonly used for TPD, according to the press release (1,2). Cresset says that design of the linkers can be a challenge in terms of optimization when accounting for not only degradation, but also both physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties.

However, to assist in this process, Enamine has compiled a library of some 5400 TPD-related linkers, available worldwide, and designed 13,000 more linker molecules. The new extension of the partnership between Cresset and Enamine refers to the integration of the linker library into Cresset’s Spark, a bioisostere replacement tool that Cresset says has been widely used for hit and lead optimization (1).

Spark uses an extended electron distribution (XED) forcefield, along with a similarity scoring algorithm, to search libraries for fragments that have similar electrostatics and shape to the scaffold or R-group of interest. The tool’s ability to “scaffold hop” allows the user to treat the linker as the scaffold to be replaced with a bioisosterically similar fragment—but because databases rarely include degrader links due to both molecule size and flexibility, Enamine’s TPD-related library permits searching for known degrader linkers, larger and more flexible than fragments in previously existing libraries (1).

“Spark is the industry's favorite bioisostere replacement tool, and the addition of these linker libraries will expand the utility of Spark to an even wider set of small-molecule drug discovery programs,” Mark Mackey, PhD, Cresset chief scientific officer, said in the release. “We are excited to continue working with Enamine to help our customers advance their projects by designing the best molecules they can.”

Cresset says early experiments have been very promising, an encouraging sign that the libraries put at users’ fingertips could prove very useful in the design of heterobifunctional molecules and molecule linkers used in TPD (1).

“We are happy to continue our productive collaboration with Cresset. Furthermore, providing streamlined access to (the) Enamine TPD-related linker library in Spark gives our joined customers a great solution for bioisosteric replacement and scaffold hopping,” said Vladimir Ivanov, PhD, Enamine executive vice president, in the press release. “Moreover, finding analogs to the linkers of interest is available via Enamine make-on-demand (MADE) building blocks, deliverable within four to six weeks, and via Enamine contract chemistry services.”

1. Cresset. Cresset Collaborates with Global Leaders Enamine to Enable the Design of Exciting New Targeted Protein Degraders. Press Release. Aug. 5, 2024.
2. Paiva, S.- L.; Crews, C. M. Targeted Protein Degradation: Elements of PROTAC Design. 

Enamine’s library of 5400 TPD-related linkers, and 13,000 more linker molecules, is now being integrated into Cresset’s Spark tool for library searching.

Cresset, Enamine Extend Targeted Protein Degradation Collaboration

Finished pharma product inspection requires stringent oversight that may be lacking in systems that rely on manual or only semi-automated processes. With the rise of automation technologies applied to biomanufacturing systems, having an automated finished product inspection system in place can make up for gaps where a lack of trained personnel may persist.

Finished product inspection starts with an evaluation of the inspection process to determine if it is able to detect defects in a pharmaceutical presentation. Once that determination is made, it is important that the inspection method is established, whether manual, semi-automatic, or fully automated. There are cases where a semi-automated or automated inspection system is not an option, which leaves manual inspection; however, if semi-automated or automated inspection options are available, then an inspection method should be determined based on lot size. In one example, lot sizes under 5000 are likely to utilize manual inspection, while lot sizes between 5000 and 15,000 would likely require a semi-automatic inspection. Above a 15,000-lot size, a fully automated inspection system is the better choice (1).

Mike Pipe, head of Global Sales & Product Management at Mettler-Toledo, points to X-ray technology as one solution in product inspection, noting that there are three main quality control issues that X-ray technology can solve in the packaging area: detection of foreign body contaminants, identifying incomplete or missing medicines, and identifying damaged packaging.

“As any responsible manufacturer knows, there can be no trade-offs in quality standards when it comes to the manufacture of pharmaceutical products. Whether the medicine is in liquid or tablet form, it is essential that foreign body contaminants are detected and removed,” Pipe states. He emphasizes that the dosage or fill levels must be correct, and that the integrity of both the packaging and the product must not have been compromised.

Pipe explains that it is now commonplace for product inspection equipment to be used in the pharma sector to overcome these challenges. “Metal detection systems can be used before tablets are pressed or packed to detect ferrous, non-ferrous, and stainless-steel metal contaminants. Vision systems and checkweighers also play a vital role in ensuring that products are complete, labeled correctly, and are at the correct weight,” he says.

Pipe points out, however, that with tablets being increasingly packaged in aluminum foil-based blister packs, metal detection systems may have a difficult time identifying if metal contaminants are present if the pharma products are inspected after packaging. “This is where X-ray technology can help. [X-ray] can detect a wide range of foreign body contaminants, including metal, both before and during packaging. It can also deliver several further quality assurance benefits,” he states.

Pipe highlights five key areas where X-ray inspection can make an important contribution in pharma production and packaging:

 As pipe points out, foreign body detection is a critical aspect of any pharma manufacturer’s product inspection operation. While metal detection is a robust inspection technology for detecting metal contaminants, including stainless steel, in the preparation or tableting process, X-ray inspection can complete contamination checks early in the production process. Using X-ray can also allow for inspection of contaminants at the final packaging stage following the blister-packing process. X-ray measures differences in absorption between low and high-density matter and can provide exceptional detection not only metal contaminants, but also glass and certain plastics and rubbers, regardless of the contaminant’s shape, size, or location within the product.

Help ensure product and packaging integrity.

 X-ray inspection can carry out a range of additional quality control (QC) tasks while simultaneously detecting foreign body contaminants, including:

Product completeness checks, including counting components and identifying damaged components—with comparison to the known number of items that should be in a pack

Identifying damaged packaging, inspecting seal quality to detect product trapped in the seal, and identifying missing components such as screw caps

Measuring product mass and comparing it to a known mass value for a reference pack

Checking fill levels—X-ray inspection images show clear discrepancies in fill levels between packs, where, for example, one pack may be under-filled and another pack may be over-filled, which can make the overall pack weight seemingly correct.

 Product recalls represent a twin-headed peril for pharma manufacturers, says Pipe. On the one hand, a product recall is costly because of wasted products and production time; on the other hand, a recall causes damage to the pharma manufacturer’s good name. “While the costs of the former are often quickly absorbed, the negative effects on brand reputation can be much more long lasting,” he notes. Therefore, implementing a well-designed X-ray inspection program can cut the risks and the costs involved in product recalls. X-ray “run codes” are assigned to each product run and can be compared to checkweigher batch data, which potentially helps isolate smaller contaminated batches that need to be recalled, instead of an entire production run.

 The absence of good product inspection can endanger patient health and safety. Such incidents can lead to major legal action being taken. Even without a worst-case scenario such as major legal action being taken; however, there is still danger posed to a pharma brand. For example, in the United States, says Pipe, pharma producers that fall foul of FDA 21 

) Part 210 (Current Good Manufacturing Practice in Manufacturing Processing, Packing, or Holding of Drugs) (2) and 21 

 Part 211 (Current Good Manufacturing Practice for Finished Pharmaceuticals) (3) are issued warning letters that are publicly available. The issuance of a warning letter can impact public trust in the brand and the brand’s reputation in the industry as well as cause extra delays and costs in bringing products to market.

 Because the pharmaceutical industry is highly regulated, compliance is critical for both patient safety and the furtherance of responsible drug supply. Quality assurance programs should therefore be robust and comprehensive, with risks identified and mitigated, Pipe says. The requirements specified in FDA’s 21 

 Parts 210 and 211 include that pharma producers must take steps to protect against contaminants getting into products and protect against damaged or compromised products reaching the market. “X-ray technology can play a key part in helping to ensure compliance, for the reasons already listed above. In addition, modern X-ray inspection systems keep digitalized records of activity, helping producers to meet the demands of 21 

 Part 11 (i.e., audit trails and digital signatures) (4),” Pipe adds.

The advantages offered by automated visual inspection include speed, precision, and consistency. An automated system can quickly process large volumes while at the same time detecting small defects, which can be missed in a manual inspection (5).

It is important to note that automated vision inspection systems have their own limitations, namely that the system’s performance is only as good as its programming. For instance, if the system has been programmed to account for every possible variation in inspection conditions, then there is a risk that it may erroneously flag safe products as defective (6). Meanwhile, there are practical considerations that may hinder widespread implementation of automated vision inspection systems across all operational scenarios. Contract development and manufacturing organizations may encounter challenges, for example, when justifying the capital investments needed (significant capital investments) and associated validation processes for implemented automated inspection. Justifying implementation could be particularly difficult when dealing with products manufactured in small batches or products that have infrequent production cycles (7).

1. Grand River Aseptic Manufacturing. Finished Product Inspection: Automation, Complex Therapeutics, and Quality Standards. 

 (Government Printing Office, Washington, DC).
3. 

 (Government Printing Office, Washington, DC).
4. 

 (Government Printing Office, Washington, DC).
5. Marsale, T. Balancing Act: Human vs. Machine Inspection in Pharmaceutical Manufacturing. 

 online, Oct. 18, 2023.
6. Yadav, V.; Kennedy, C. Vision Inspection Using Machine Learning/Artificial Intelligence. 

. November/December 2020.
7. Melchore, J. A. Sound Practices for Consistent Human Visual Inspection. 

 (1), 215–221. DOI: 10.1208/s12249-010-9577-7

®
Vol. 48, No. 8
August 2024
Pages: 29–30

When referring to this article, please cite it has Mirasol, F. Considerations for Finished Product Inspection Systems. 

Manual and automated inspection technologies have their own advantages and limitations.

Considerations for Finished Product Inspection Systems

On Aug. 1, 2024, Freudenberg Medical announced  an expansion to its biopharma product portfolio, which now includes custom single-use assemblies. The assemblies will be combined with the company’s expertise in silicone extrusion and molding. Included in the new offerings are single-use Y-connector manifolds, tubing assemblies, and bottle cap assemblies with multiple inlets/outlets. Both labs and current good manufacturing practice (CGMP) bioprocesses commonly use bottlecap assemblies with Y-connector tubing for critical fluid transfer applications, according to the company in a press release.

The assemblies are cleanroom manufactured according to customer specifications. Among the advantages, Y-connector overmolds offer unobstructed flow within a critical fluid path and can prevent leaks from occurring. Leaks are commonly seen with standard fluid couplings, fittings, and connectors, according to Freudenberg. “Validated production processes with proven process capabilities will continuously ensure consistent overmolding of Y-manifolds on customer-specified tube ends,” the company stated in the press release.

The expanded biopharma portfolio complements the company’s existing PharmaFocus Premium product line containing high purity, platinum-cured silicone tubing and sanitary ends for single-use systems. The company’s tubing, molded components, and systems are used in bioprocessing, biotechnology, lab processes, GMP manufacturing, small batch processes, and cell and gene therapy as well as for the production of messenger RNA, biosimilars, and regenerative proteins.

The company’s other expansion activities include a $50 million investment in a new Hemoteq AG production facility in Aachen, Germany, to expand its coatings business (1) and a $25 million investment to establish a manufacturing site in Costa Rica (2). The expansion in Germany, which Freudenberg announced in June 2024 will triple its manufacturing footprint with a new 130,000-ft

 facility in Alsdorf, near the existing site. The new facility houses ISO Class 7 cleanrooms, laboratories, and offices and will serve as a hub for R&D and production as well as drive innovation in medical coatings (1).

The new Costa Rica facility, announced in February 2024, is slated to come online in the beginning of 2025 and will be dedicated to assembling high-volume minimally invasive catheters for electrophysiology, vascular and structural heart therapies, and other medical devices requiring high-precision manual assembly. The first phase of construction comprises a build on 50,000 ft

 and the facility will house three ISO 7 cleanrooms. The company also expects to add another 50,000 ft

 to the site within three years of its opening. This added construction will quadruple Freudenberg’s total footprint in Costa Rica (2).

Of the Germany site expansion, Mark Ostwald, CEO of Freudenberg Medical, said in a company press release issued at the time, "The convergence of medical devices and drugs is inspiring a new generation of innovative products that fundamentally improve patients’ outcomes. With this innovation driven investment, we are strengthening our position as a strategic partner to our customers, offering vertically integrated solutions along the entire supply chain" (1).

Meanwhile, Róger Gómez, vice-president/general manager of Freudenberg Medical in Costa Rica, said of the Costa Rica facility expansion at the time it was announced, “The investment in this new site underlines Freudenberg Medical’s confidence in Costa Rica as an integral part of our global growth strategy. In the next three years, we will triple the number of employees from the current 300 to over 900 team members. Committed to diversity and inclusion, we offer equal opportunities to all” (2).

1. Freudenberg Medical. Freudenberg Medical Expands Coatings Business with New Production Facility. Press Release, June 11, 2024.
2. Freudenberg Medical. Freudenberg Medical Establishes Second Production Facility in Costa Rica. Press Release, Feb. 14, 2024.

Freudenberg Medical has introduced custom single-use assemblies for silicone extrusion and molding for biopharma applications.

Freudenberg Expands Biopharm Product Portfolio with Addition of Custom Single-Use Assemblies

Cheryl Barton is director of PharmaVision, 

Landkarte *** Europa | Image credit: ©beugdesign - Stock.adobe.com

On 3 July 2024, the Health Committee of the Bundestag amended and approved the Federal Government’s Medical Research Act (Medizinforschungsgesetz or MFG) (1). The new legislation will impact national laws to simplify clinical trials and approval processes for drugs and medical devices. MFG will also amend rules on advanced therapy medical products (ATMPs) and drug pricing and reimbursement laws (Arzneimittelmarktneuordnungsgesetz [AMNOG]). In addition, the new legislation will result in a reorganization of the regulatory agencies (The Federal Institute for Drugs and Medical Devices [BfArM] and Paul Ehrlich Institute [PEI]) and ethics committees (2).

Pharma may choose confidential pricing … but at a cost

The MFG allows pharmaceutical companies confidential pricing, providing they have drug research departments in Germany that can demonstrate “relevant own projects and cooperation with public institutions in preclinical or clinical drug research in Germany” (3). For instance, if at least 5% of approved study subjects participate in clinical trials in Germany, then manufacturers could be exempt from the AMNOG guardrails that were introduced with the Statutory Health Insurance Finance Stabilization Act in November 2022 (4).

Once a pharma company has completed price negotiations with the National Association of Statutory Health Insurance Funds (GSK-SV), they will have five days to decide whether to keep the pricing of new patent-protected drugs confidential or transparent. Within seven days of receipt, the GSK-SV will decide whether ‘sufficient’ proof has been provided. If a pharmaceutical company requests confidential pricing, an additional discount of 9% will be imposed on the agreed sales price (not the pharmacy sales price) (3).

Companies that opt for confidentiality will also be obligated to reimburse the health insurance funds and other payors the overpaid difference between the ‘public’ and the ‘real’ price and will also have to reimburse the health insurance funds the overpaid portions of the mandatory surcharges for pharmacies and wholesalers and value-added tax (VAT) (3). Therefore, the final price negotiated by companies to keep drug prices secret could result in more than the 9% discount. The new rules for confidential reimbursement prices shall apply as of 1 Jan. 2025 and will be enforced until 28 June 2028 and reviewed in late 2026 (3).

Confidential pricing has proved a contentious issue among stakeholders in Europe. On one hand, the pharma industry in Europe has been keen to move towards confidential pricing because German reimbursement prices are regularly used as reference prices in other European countries, and an unfavourable price in Germany can have a significant impact on the price achieved in other European countries and abroad. In the past, this has led manufacturers to withdraw drugs from the German market; for instance, Bristol Myers Squibb decided not to launch the cancer drug Opdualag (nivolumab/relatlimab combination) in Germany, due to pricing pressures (5). If a company chooses to keep the reimbursement price confidential, it would not be listed in public sources or disclosed to pharmacies and could lead to differential pricing, the ‘public’ price, and the ‘real’ or agreed (discounted) price (3).

In 2022, the ‘AMNOG guardrails’ regulations were introduced to protect against excessive prices for patent-protected drugs with no or only a small or non-quantifiable benefit (6). These regulations will be deleted and replaced by the economic development goals laid out by the German Government in its new Pharma Strategy (6,7). However, the GSK-SV fears the lack of transparency could lead to increases in pharmaceutical expenditure (8,9). This is a major concern given that more than 73 million German citizens with statutory health insurance have already witnessed a significant increase in health insurance contributions earlier this year, and there is pressure on the Federal Ministry of Health to raise contributions further (6).

The new Pharma Strategy aims to make Germany more attractive to the pharma industry

The MFG is part of the German government’s National Pharma Strategy to strengthen Germany’s position as a business and pharmaceutical location (10). The Strategy Paper 4.0–Improving the General Conditions for the Pharmaceutical Sector in Germany lists several specific reform ideas all of which will have a significant impact on the pharmaceutical industry and aim to improve market access and pricing environment in Germany (Figure 1).

Figure 1: Strategy Paper 4.0 points of reform. Source: modified from (10). Figure courtesy of the author.

Germany is the fourth largest pharmaceutical market in the world and the largest European market generating €56.5 billion in 2022 and growing by 5.4% per annum (11). According to Marcus Schmidt, Germany Trade & Invest Director of Chemicals and Health, “The pharmaceutical strategy underlines the great importance of this sector for the federal government. Together with the laws that have already been introduced, Germany will expand its leading role in Europe in the areas of research and development as well as production” (10). Several pharma companies—Daiichi-Sankyo, Eil Lilly, and Sanofi—have all increased their investment in Germany in the past nine months (12).

The latest reform could have a significant impact on drug pricing and will link it more closely to local investment in clinical trials and R&D in Germany. However, the MFG will not come into force until it has received the seal of approval from the German Federal Council (Bundesrat), and this is unlikely to occur until the fourth quarter of 2024 (3).

 Entwurf eines Medizinforschungsgesetze Drucksache 20/11561. 29 May 2024.

Germany Amends Drug Pricing and Reimbursement Laws with the “Medical Research Act”–Drug Pricing Becomes Intertwined with Local Clinical Research Expectations.

 Blog. Insideeulifesciences.com. 12 July 2024.

Health Committee Approves Medical Research Act.

Simon-Kucher. Germany: How the GKV-FinStG Law is Transforming the Pharma P&R Landscape. Simon-kucher.com. 24 Feb. 2023.

Are German Drug Pricing Regulations Chasing Some Drug Makers Away, Causing Them To Not Launch Products In The Market?

Health Insurance Companies Should Support the Pharmaceutical Industry

German Government Pursues New Pharma Strategy with Significant Reform Ideas

. Blog. Covington. Insideeulifesciences.com. 21 Nov. 2024.

Secret Prices Make Care More Expensive Without Improving It

. GKV. GKV-spitzenverband.de. 6 June 2024.

What are the Implications of Confidential Rebates in Germany?

Big Changes Coming in German Health, Pharma, Pharmaceuticals

. Germany Trade and Invest, GTAI. gtai.de 14 Dec. 2023.

. Germany Trade and Invest, GTAI. gtai.de (accessed 12 July 2024).

Germany’s New Medical Research Act Will Allow Pharma Companies Confidentiality on Price

Cheryl Barton, PhD, is director of PharmaVision, info@pharmavision.co.uk.

®
Vol. 36, No. 7
July/August 2024
Pages: 9–10

When referring to this article, please cite it as Barton, C. Germany Amends and Approves the New Medical Research Act. 

Germany’s Medical Research Act allows pharmaceutical companies to keep drug prices confidential.

Germany Amends and Approves the New Medical Research Act

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Tecelra (afamitresgene autoleucel), a first-of-its-kind gene therapy for the treatment of synovial sarcoma made by Adaptimmune, was approved by FDA on Aug. 2, 2024 for use in adults with an unresectable or metastatic case of this rare form of cancer and who have received prior chemotherapy, are positive for certain human leukocyte antigens (HLA), and whose tumor(s) may express melanoma-associated antigen (MAGE)-A4 as determined by a diagnostic device (1).

According to a press release from FDA, Tecelra is also the first FDA-approved T-cell receptor (TCR) gene therapy, an autologous immunotherapy composed of a patient’s own T cells, which are modified to express a TCR that targets MAGE-A4 (1). As an immune system trigger, that antigen is normally expressed by cancer cells in synovial sarcoma; among the other antigens for which Tecelra patients may be positive are HLA A*02:01P, -A*02:02P, -A*02:03P, and -A*02:06P.

Synovial sarcoma, which affects about 1000 people annually in the United States, most of them adult males under the age of 40, is a cancer in which malignant cells develop and form into a tumor in soft tissue, most often in the extremities, although it can be found in all parts of the body, and cancerous cells can spread throughout the body as well (1). It is treated with surgery to remove the tumor, followed by radiotherapy and/or chemotherapy if the tumor is large, has returned after being removed, or has metastasized.

“Adults with metastatic synovial sarcoma, a life-threatening form of cancer, often face limited treatment options in addition to the risk of cancer spread or recurrence,” said Nicole Verdun, MD, director of the Office of Therapeutic Products in FDA’s Center for Biologics Evaluation and Research (CBER), in the press release. “Today’s approval represents a significant milestone in the development of an innovative, safe, and effective therapy for patients with this rare but potentially fatal disease.”

FDA’s Accelerated Approval pathway provided Tecelra with an opportunity to be approved while Adaptimmune conducts further trials to verify the therapy’s predicted benefit, and one such confirmatory trial is currently ongoing (1). Accelerated Approval allows FDA to move certain drugs forward for treatment of conditions or diseases that are serious or life-threatening and have an unmet medical need, and for which the drugs’ effects on surrogate endpoints have been beneficial (2). In a multicenter, open-label clinical trial, Tecelra produced a response rate of 43.2% among 44 patients, with six months as the median duration of response, according to FDA.

“Potentially life-threatening cancers such as synovial sarcoma continue to have a devastating impact on individuals, especially those for whom standard treatments have limited efficacy due to tumor growth and progression,” said Peter Marks, MD, PhD, director of the CBER. “The approval of this state-of-the-art immunotherapy technology provides a critical new option for a patient population in need and demonstrates the FDA’s dedication to the advancement of beneficial cancer treatments.”

1. FDA. FDA Approves First Gene Therapy to Treat Adults with Metastatic Synovial Sarcoma. Press Release. Aug. 2, 2024.
2. FDA. Accelerated Approval. 

Synovial sarcoma is a rare form of cancer impacting about 1000 adults in the United States each year, most of them men in their 30s or younger.

First Gene Therapy for Adults with Metastatic Synovial Sarcoma Approved by FDA

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Contract organizations offer sponsor companies flexibility by providing capacity, expertise, knowledge, and cost savings. Contract manufacturing organizations (CMOs), contract development and manufacturing organizations (CDMOs), and other contract organizations can also offer smaller bio/pharma companies greater opportunities, by providing the resources smaller biopharma companies may not have. According to Robert O’Brien, director operations—Packaging & Logistics at Almac Pharma Services, sponsor companies should consider if contracting activities to a CMO is more cost effective than performing those activities in-house. O’Brien points to direct access to specialists and equipment, a level of control of quality standards, and requirements for scale up as factors to consider when deciding whether to outsource or not. “Outsourcing enables the sponsor company to concentrate on their core competencies, product innovation, and strategic initiatives,” O’Brien says.

When making the decision to outsource a particular process to a contract partner, there are several things sponsor companies should consider. Tech transfer is an important step when outsourcing to a CDMO and should be evaluated when choosing to outsource processes, specifies Peter Ercoli, chief operating officer, Biologics, at BIOVECTRA. Ineffective tech transfers can lead to persistent complications, adds Ercoli. “Conversely, sponsors should ensure their processes are completely defined before initiating a tech transfer, unless they want the CDMO to define it for them. In the case where sponsors are leaning on the CDMO to define their tech transfer process, both parties must be clear on this understanding from the outset,” he says.

Not following regulatory requirements can also complicate the situation when working with CDMOs, according to Ercoli. “The last thing a sponsor wants is to successfully complete the tech transfer and scale-up phases only to fail a pre-approval inspection. Such a failure can be catastrophic, potentially setting back the project by months or even years. While other challenges can be managed with guidance or collaboration, the readiness of facilities and personnel for regulatory inspections is non-negotiable and must be thoroughly vetted,” he says.

The benefits of an outsourcing partner extend to most, if not all, aspects of development and manufacturing, and analytical testing is no different. “CDMOs amass a great breadth and depth of knowledge through their exposure to a wide range of product types including small molecules, peptides, biologics, conjugates, highly potent, and controlled substances,” says Susan Hackett, associate director—Technical Operations, Almac Sciences. “Additionally, not all companies have the appropriate infrastructure to accommodate analytical testing; therefore, outsourcing these operations to an established CDMO helps to save time and cost.”

Outsourcing finished product testing is beneficial for sponsors, because it can provide unbiased results, according to Shailesh Vengurlekar, senior VP Quality & Regulatory Affairs, at LGM Pharma. Sponsor companies should consider the quality of the work and the data provided by a contractor when selected a testing partner. Turnaround time, infrastructure, cost, and communication are also key, according to Vengurlekar.

“Sponsors typically benefit most when outsourcing complex testing services that they may not have the capability (equipment, personnel expertise, time, etc.) to perform in-house,” says Vengurlekar. “[Whereas], it is also beneficial to sometimes outsource simple and routine testing involving a lot of the sponsor’s time and labor. The time can be better utilized by the Sponsors to develop their product database as well as on timely submissions to meet company goals.”

A robust methodology can be achieved by outsourcing method development and validation, remarks Hackett. “As the drug develops, working with a provider who has a dedicated team utilizing orthogonal techniques such as mass spec[trometry], ID testing, can be hugely beneficial and help to resolve any issues much quicker,” says Hackett. “For finished product testing, outsourcing to a partner who has the capability, capacity, and resources to manage all testing aspects together can alleviate many of the issues which inherently arise during drug development.”

Hackett stresses that both the sponsor and the contractor are responsible for analytical testing and should maintain good communication. “Ensuring that there is equivalent equipment between the labs is an obvious solution, and that the methods are fully understood by both teams,” she says. “Robust processes, particularly with method transfer and familiarization, should also ensure the chances of success. However, as stated, having access to a team who are well experienced in orthogonal techniques can be hugely beneficial if [testing failures] occur to conduct deeper analysis to troubleshoot and find a resolution,” says Hackett.

“[Testing results] may vary [from sponsor to contractor] if the method transfer has been incorrectly performed or same methodology/equipment are not used by testing laboratories. Significant variations or laboratory errors are observed due to lack of proper training, poor quality of protocols, or detailed procedures,” says Vengurlekar. “Typically, collaboration between both parties is required to investigate the results from both ends to determine the true value. The sponsor should always take the lead to investigate the root cause and guide contractor labs to put appropriate corrective and preventive actions (CAPAs) in place.”

Packaging is one of the final steps when manufacturing a bio/pharmaceutical product and sending it out to the market. The quality of a product can be compromised by a variety of factors, including temperature; therefore, O’Brien notes that packaging materials should be carefully selected. Other challenges include labeling and serialization requirements.

Packaging providers can provide cost savings by sparing a sponsor from having to invest in equipment, facilities, personnel, and a broad network of suppliers, according to O’Brien. Contractors may offer state-of-the-art technology and staff training, he states. “[O]utsourcing allows sponsors to achieve scalability and flexibility, enabling them to scale their packaging operations up or down based on demand. This flexibility is crucial for adapting to market fluctuations and growth opportunities,” O’Brien states.

Contracting out packaging services can also offer a layer of quality control. Contract packagers offer experience with regulations in various territories and can help ensure safety and quality standards are correctly met, specifies O’Brien. “External partners often have robust quality control systems in place. This ensures that packaging adheres to industry and highest quality standards ensuring products maintain stability throughout the supply chain,” he says.

When partnering with a contract packager, O’Brien stresses that specifications, timelines, and quality standards must be aligned with both parties. “Risk management is a key concern—it’s vital to mitigate potential disruptions to the supply chain that may arise due to unforeseen events. Quality control is similarly critical—consistency and compliance across the packaging process must be maintained. Cost management—balancing cost-effectiveness with quality—is a perpetual consideration,” says O’Brien. “Lastly, intellectual property protection must be addressed to safeguard proprietary information during collaboration. Overall, these challenges can be overcome through close collaboration, transparency, and clear agreements between both parties to ensure successful outcomes.”

Partnerships don’t always work out. But what if that partnership is the development and/or manufacture of an important drug product? If a sponsor company must change from one contract manufacturer to another when a project is already underway, what challenges may they face? Transferring mid-project from one contract to another requires close coordination, according to O’Brien, to minimize delays and costs.

“Proactive planning and open communication including full, and early, transparency regarding any concerns, is key to overcoming these challenges,” says O’Brien. “In addition, rigorous quality control measures are essential to ensure consistent quality between the existing and new provider. Finally, internal and partner teams should be cautious and thorough when migrating data, documentation, and intellectual property to avoid delays and errors during the transition. Both parties need to adjust to new processes, communication channels, and expectations therefore continual briefing, communication and escalation, where required, is essential throughout.”

“When switching from one CDMO to another during a project, the new partner or CDMO should be given access to communicate with the innovator directly,” says Ercoli. “This approach allows for a clear understanding of the development context and enables questions to be answered accurately. Direct access to the innovator ensures that the original intent of the project is preserved. Otherwise, transitioning from one CDMO to another often results in miscommunication. The process can resemble a game of ‘telephone’, where information is passed along through multiple intermediaries, leading to potential distortions. By the time the message reaches the new CDMO, the original intent may be lost, complicating the project further. To mitigate these risks, all parties involved should strive to keep open lines of communication as much as possible during the transition.”

Outsourcing can provide a variety of benefits for a sponsor, whether the outsourced service is testing, packaging, manufacturing, or another process in the lifecycle of the product. If a sponsor chooses to outsource work, they should keep quality in mind. Contractors will most likely have several customers; therefore, sponsors should look for customized quality control (1).

“When CDMOs develop quality agreements with a greater focus on client needs, it can increase trust, compliance, and even make audits easier to manage. Complex procedures can be simplified by engaging all parties and clearly documenting in the quality agreement from the start. While this may add initial time and cost, over the long run this will pay out with less process issues, including errors or oversights,” said Iain McGhee (1).

Taking these factors into consideration can help a sponsor company create the best outsourcing strategy for the company, the product, and the patient.

1. McGhee, I. Ensuring Quality in Contracted Support. 

BioPharm International Partnerships for Outsourcing eBook.

®
Vol. 48, No. 8
August 2024
Pages: 31–33

When referring to this article, please cite it as Haigney, S. Contracting Out Frees Sponsors Up. 

Contract organizations offer sponsors specialized equipment, capacity, and expertise for testing, manufacturing, and packaging bio/pharmaceutical products.

Contracting Out Frees Sponsors Up

Over the past two decades, 32 cell and gene therapies (CGTs) have been approved by the regulatory authorities worldwide, and more than 2000 novel products are under clinical investigation (1). However, many patients do not have access to these life-saving therapies, partly due to the complexity and high cost of manufacture (2). But how can CGTs be made more cost-efficient given the high labour and facility costs?

According to Miguel Forte, CEO, of Kiji Therapeutics, France, and president of the International Society for Cell & Gene Therapy, “It is clear that CGTs have the opportunity to deliver enormous value to patients; nonetheless, manufacturing is complex, and it has been challenging to deliver the product. Innovative technologies and services have enabled the industry to move towards an automated, closed-system approach that is easier and safer to operate and is less costly and closer to the patient.”

Cell therapies can be derived ex vivo from autologous cell therapies (patient to patient), allogenic cell therapies (donor to patient), or in vivo cell therapies (cell line to patient). Each approach requires manufacturers to tailor the biomanufacturing process to generate specific cell types (and/or vectors), safely, efficiently, and cost-effectively. Manufacturing tools have tended to lag behind scientific advances in CGTs leading to bottlenecks in cell production. Currently, most CGT manufacturers use disconnected single-step/modular or semi-automated solutions; however, the industry is migrating towards fully automated cell therapy manufacturing processes (3). And this approach could significantly reduce manual intervention, risk of contamination, and human error; improve product quality and speed of delivery; and reduce production costs (4).

According to David Smith, vice president of Development, BioCentriq, “Labour costs, and facility costs are sky high, which have led to high price points, particularly in autologous cell therapies where production is 1:1. Automation is a key part of improving costs, reducing labour both in and outside the clean room, and implementing release by exception can help to reduce bottlenecks. Companies are trying to integrate unit operations whether it’s an ‘all-in-one-box’ approach or a ‘unit-operator’ approach where units can be plugged in or out and are integrated within robotic systems to offer greater flexibility.”

For instance, Lonza’s Cocoon Platform and Miltenyi Biotec CliniMACS Prodigy offer an ‘all-in-one-box’ approach providing a closed, automated system for patient-scale cell therapy manufacturing from cell isolation, activation, transduction/transfection, expansion, and harvest within a validated cell manufacturing system (5,6). CliniMACS Prodigy modular Instruments can also be run in parallel to provide large-scale batch production.

UK-based Ori Biotech launched its IRO platform developed in 2024 in collaboration with CTMC (a joint venture between Resilience and MD Anderson Cancer Center). This platform automates the activation, transduction, expansion, and harvest of a wide range of cell types to rapidly scale up manufacturing from the clinic to the commercial setting (7).

Paris-based Astraveus SAS has developed the Lakhesys Benchtop Cell Factory, an end-to-end solution for the manufacture of adherent, non-adherent, and inducible pluripotent stem cells (iPSCs) (8). The company has raised €16.5 million in seed financing and received a €10.4 million grant from the French government as part of its “Innovation in Biotherapies and Bioproduction” initiative, to advance the development of its technology (9).

Several companies are developing integrated bioreactors, robotic systems, and smart monitoring technologies that can support a ‘unit operator’ approach.

UK-based Cellular Origins, launched Constellation, a closed fully automated, and configurable robotic platform for CGT manufacture in 2023 (10). In May 2023, it forged a partnership with ScaleReddy (a joint venture between Bio-Techne, Fresenius Kabi, and Wilson Wolf) to automate its CGT manufacturing workflow using Cellular Origin’s robotic system (11). According to Jason Jones, Global Business Development lead, Cellular Origins, “Our company integrates existing, proven technologies with mobile robotics to provide fully automated factories that can be scaled up to manufacturers’ requirements, minimize risks, and are GMP [good manufacturing compliance] compliant. We can achieve a 30-fold increase in space efficiency and manufacture and a 16-fold labour reduction, equating to a 51% reduction in cost-of-goods and enabling manufacture 24/7, 365 days a year.”

Swiss-based Limula has taken a different approach and developed a modular solution that combines a bioreactor and centrifuge into one device for on-demand and at-scale manufacturing of cell therapies (12). In May 2024, the company raised CHF 6.2 million (US$6.8 million, €6.24 million) in seed funding to develop its automated CGT manufacturing platform, the funding round was over-subscribed highlighting the interest that venture capitalists have in this field (13).

UK-based MicrofluidX has developed a space-saving stackable multi-bioreactor instrument—the Cyto Engine Stack. Each bioreactor can be controlled and monitored independently, to allow cell therapy manufacturers to expand their manufacturing capacity without increasing the facility footprint. The first Cyto Engine product is scheduled for launch in early 2025 (14).

Other companies have focused on leveraging digital tools and advanced analytics to streamline the manufacturing process. For instance, UK-based Autolomous has launched AutoloMATE Launchpad, a cloud-based CGT platform that allows for the scalability and adaptability of different CGT modalities (15). According to Alexander Seyf, the CEO of Autolomous, “Addressing manufacturing challenges effectively demands a shift towards more integrated and automated systems. By leveraging digital tools and advanced analytics, we can enhance process control, increase reproducibility, and reduce labour-intensive procedures which, in turn, decrease costs significantly. Moreover, digitization can streamline data flow across the manufacturing process, ensuring that critical information is accessible and actionable. This integration leads to improved decision-making, faster turnaround times, and ultimately, more standardized production of therapies.”

In 2024, US-based Cellares, became the first Integrated Development and Manufacturing Organization (IDMO) to offer a high-throughput fully, automated smart manufacturing platform Cell Shuttle. In April 2024, the company signed a US$380 million (€349 million) supply agreement for the manufacture of chimeric antigen receptor-T cell therapies with Bristol-Myers Squibb, and it announced a similar agreement with Kite in June (16,17).

Over the next decade, the demand for CGTs is expected to grow as they move further up the treatment cascade and target more common diseases. It will be essential for companies to address the challenges associated with scaling up the manufacturing process to provide high-quality, consistent autologous and allogenic cell products while adhering to stringent regulatory standards. Fully automated space-saving modular technologies will allow manufacturers to steadily scale up capacity and adapt to demands (18).

Smith notes, “CDMOs [contract development and manufacturing organizations] are looking at the trajectory of pipeline products and questioning where and when they need to invest in new facilities and technologies. Manufacturing is one of the biggest areas of risk in CGT developments, but if we can de-risk the process by deploying robust engineered manufacturing processes and automation, we can reduce the cost of autologous cell manufacture and increase the speed and flexibility to meet individual needs. On the allogenic side, the processes tend to be on a larger scale, and the drug product cost is shared amongst many patients. Although automation can assist in cost reduction, the burden is less steep than for autologous, that said, many of the same automation tools can be used across processes, and the industry is looking to standardize manufacturing.”

In the longer term, the industry could move towards a more decentralized manufacturing model that utilizes automated point-of-care technologies to enable on-sitepreparation of CGTs in or near hospitals, helping to bring therapies closer to the patient.

“The current acute unmet need is on scaling centralized systems, but we’ve had some interesting conversations around decentralization negating operator variability/increasing process comparability and digitalization of information of the product and opening up facilities at the national, regional, and near-hospital levels depending on the therapy and medical need,” observes Jones.

Gene, Cell, and RNA Therapy Landscape Report.

 Q1 2024 Quarterly Data Report. 11 Apr 2024.

Harrison, P.T., Friedmann, T. Correction: Cost of Gene Therapy. Gene Therapy, 2024, 31, 195-196.

Closed, Automated Cell Therapy Manufacturing–Is Your Facility Ready?

Harris, R. Cell Therapy Manufacturing Shifts to Automatic. Genetic Engineering & Biotechnology News. 4 Oct 2021.

The Cocoon® Cell Therapy Manufacturing Platform.

 miltenyibiotec.com (accessed July 2024).

Ori Biotech Unveils IRO Platform at Annual International Society for Cell & Gene Therapy Conference

Lakhesys™ Benchtop Cell Factory - Astraveus - Enable a Healthier Tomorrow

PRNewswire. Astraveus Raises €16.5 Million Series Seed Round to Advance the Development of its Automated, Microfluidic Cell and Gene Therapy Manufacturing Platform. News Release. 27 Jun 2023.

Cellular Origins Launches Constellation™, Its Configurable Robotic Platform to Enable Scalable Manufacture of Advanced Therapies

Cellular Origins Partners with ScaleReady to Simplify, Standardize, and Automate Cell Therapy Manufacturing

Innovative solutions are making personalized cell and gene therapies accessible to all.

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